The health and economic impact of osteoporosis continues to make studies of bone resorption by osteoclasts a critically important research focus. Osteoclasts are exceptionally dependent on vesicular trafficking, which is essential for bone resorption. Consequently, disruption (genetic or pharmacological) of osteoclastic vesicle transport abolishes resorptive activity. Proteins of the Snx family are known to mediate endosomal sorting, endocytosis, recycling of membrane proteins, and trafficking between various endosomes and Golgi apparatus. We found Snx10, a family member expressed in osteoclasts and in the stomach, where it is required for acid production. We generated Snx10-deficient mice (Snx10ins/ins) via gene-trap technology and characterized the bone phenotype. Snx10ins/ins mice exhibit a complex phenotype that is a combination of osteopetrosis (due to impaired osteoclast resorption) and rickets (impaired mineralization due to impaired gastric acidification and poor calcium absorption) known as osteopetrorickets. The underlying mechanisms leading to osteopetrorickets are currently unknown. Based on these findings, we conclude that Snx10 is essential for bone homeostasis in vivo by regulating vesicular trafficking and therefore acid production in both osteoclasts and the stomach. In this proposal we will use cell-specific Snx10 ablation studies in bone and stomach to elucidate the molecular mechanisms by which Snx10 regulates both osteoclastic resorption and gastric acidification for bone homeostasis. This proposal has high significance as it will characterize a new candidate gene involved in the development of human bone diseases, including osteoporosis, and bone loss associated with calcium deficiency. These results will change the paradigm of therapy for osteopetrotic patients with mutations in Snx10 and other genes with similar patterns of expression and activities, whose gastric defect has been generally overlooked. Importantly, our findings will significantly advance our understanding of the molecular mechanisms controlling osteoclast function and the control of bone homeostasis by the gastrointestinal tract.